Ionizing radiation is an important modifier of the tumor microenvironment that has been shown to have the potential for therapeutic synergy with immune response modifiers both in pre-clinical studies and some initial clinical studies. This emerging evidence suggests a new paradigm in the clinical use of radiotherapy whereby the goal transcends the local tumor control to evolve toward the induction of an immunogenic tumor cell death, resulting in an "in situ" form of individual vaccination. Ionizing radiation also induces key soluble cytokines and chemokines, as well as phenotypic changes in irradiated tumor and stroma further contributing to immune-mediated tumor rejection. Conversely, radiation induces expansion of immune-regulatory cells populations that may have relevant immune-suppressive effects, that could be counteracted with currently available drugs.

Overall, the ability of radiation to promote both, the priming and effector phase of the anti-tumor immune response provide a compelling argument for exploring these yet unexploited features in the clinic. However, many questions remain to be addressed before the use of radiation as an immunological adjuvant becomes a clinically available strategy . For instance, relatively limited information exists about which radiation regimens generate the optimal balance between induction of immune-stimulatory versus immune-suppressive pathways. Moreover, the choice of the immune therapies that best synergize with radiation, and their optimal sequencing are undefined.

The articles in this focused issue will illustrate examples of promising combinations between radiotherapy and immune response modifiers that have been tested in pre-clinical models, and early clinical trials.